Omalizumab is a 149-kDa humanized monoclonal antibody obtained using recombinant DNA technology. It is an IgG1 type antibody composed of human (95%) and murine (5%) fractions.5 The latter is the active fraction, and is minimized to prevent anaphylactic responses.

The antibody binds to the C¿3 domain of human IgE (Fig. 2), very close to the binding site for high and low affinity IgE receptors (Fc¿RI and Fc¿RII, respectively). Omalizumab can bind to free IgE in serum or interstitial fluids, but not to IgE molecules that are bound to the cell surface, as in this case the omalizumab binding site is occupied by the receptor.6

Figure 2.

Binding of omalizumab to the c¿3 domain of IgE.

(0.08MB).

Omalizumab has two mechanisms of action:

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  Reduction of free IgE levels in plasma. Omalizumab binds to a region in the IgE molecule that overlaps with the site through which IgE binds to its receptor on target cells (basophils and mast cells), regardless of IgE specificity. This results in the formation of small complexes (trimers or hexamers of less than 1000 kDa) that are biologically inert (ie, do not activate complement) and are slowly eliminated via the reticuloendothelial system. In the case of high affinity receptors present on basophils and mast cells, omalizumab blocks IgE-Fc¿RI binding and prevents cellular activation and the release of vasoactive substances such as histamine and other inflammatory mediators such as leukotrienes, tryptase chymase, prostaglandin D2, and cytokines.7 These substances are responsible for the characteristic clinical features of nasal, conjunctival, bronchial, and skin hyperreactivity reactions.

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  Indirect reduction of the number of Fc¿RI receptors in target cells.8This effect is considered secondary to the elimination of serum IgE. Previous studies have shown a strong correlation between total serum IgE levels and Fc¿RI expression on basophils in peripheral blood; receptor expression is significantly reduced when these cells are cultured in the absence of IgE.9,10 Similarly, Fc¿RI expression on basophils is greatly reduced in mature bone marrow cells exposed to a very low levels of IgE. A pharmacokinetic study demonstrated a mean decrease of 73% in Fc¿RI expression with maximum inhibition after 14 days of treatment with omalizumab.11 This reduction in the number of high affinity receptors may explain the efficacy of omalizumab in the treatment of chronic autoimmune urticaria, as the number of target receptors for anti-Fc¿RI antibodies is decreased.

However, some clinical and laboratory data suggest that the mechanism of action of omalizumab is multifactorial and that the drug may act on other, less well-known, target cells in the immune system. Sanchez-Machín and coworkers12 reported increased activity of CD4+ T lymphocytes in the serum of a patient with non-autoimmune chronic urticaria who responded rapidly to a regimen of 300 mg omalizumab every 2 weeks. Moreover, Iemoli and colleagues13 reported reduced B cell activation, decreased TNF-α and IL-4 levels, and increased IFN-γ synthesis in the serum of another patient with chronic idiopathic urticaria who was treated with omalizumab.

Omalizumab is available in prefilled syringes for subcutaneous administration. It is available in 2 doses: 75 mg and 150 mg. The patient's pretreatment serum IgE level (IU/mL) and body weight (kg) are used to determine the appropriate dose (mg) and dosing frequency. The approved dose of the drug for the treatment of asthma is 0.016 mg/kg/IgE (IU/mL), provided that pretreatment IgE levels do not exceed 1500 IU/mL. The use of this omalizumab treatment regimen is associated with a reduction in IgE levels of approximately 95% from baseline in the first 3 days of treatment.14 The same dose is usually re-administered at 2 or 4-week intervals for up to 16 weeks. Treatment with the recommended dose of omalizumab produces a rapid decline in serum IgE levels to less than 50 ng/mL (20.8 IU/mL). In the treatment of allergic asthma and rhinitis, low serum IgE levels have been associated with beneficial effects, and the benefits can last up to several months or as long as IgE levels remain low.15 Omalizumab has a half-life of 26 days with an average clearance of 2.4 ± 1.1 mL/kg/d via the reticuloendothelial system. The effect of omalizumab can last for several months. There is no need to adjust the dose for age (12-76 years), race/ethnicity, or gender.

Omalizumab appears to be a safe and well-tolerated drug. Few adverse effects have been reported and most of them are minor. The most common adverse reactions reported during clinical trials were skin reactions at the injection site and urticaria. Skin reactions, such as pain, swelling, erythema, and pruritus, occur in about 40% of patients16 and urticaria is reported in 4.9% of patients.17Table 1 lists the adverse reactions, recorded in patients treated with omalizumab in clinical trials, by organ system and frequency.

The most feared adverse reaction is anaphylaxis, which is mediated by the murine fraction of omalizumab. In 2007, the American Academy of Allergy, Asthma, and Immunology created the Omalizumab Joint Task Force to record data on omalizumab-associated anaphylaxis. The Task Force found an incidence of anaphylaxis of 0.2%, with 61% of such reactions occurring within 2 hours of the first 3 injections and 14% within 30 min of the fourth or subsequent injections. In line with these observations they established the following recommendations for all patients treated with omalizumab (Table 2).18

If these recommendations are followed, 77% of anaphylactic reactions can be detected in advance and treated appropriately.19

Omalizumab was evaluated in an extensive program that included 12 Phase IIB and Phase III clinical trials involving over 5243 patients treated with omalizumab for severe IgE-mediated asthma and rhinitis. These studies concluded that the safety profile of omalizumab was comparable to that of the control group and of standard therapies with H1 antihistamines, and found no increase in the risk of cancer in omalizumab-treated patients.20 Moreover, a recent review of the incidence of primary tumors in 32 randomized, double-blind, placebo-controlled trials concluded that there was no statistically significant association between treatment with omalizumab and the development of cancer.21

The FDA is currently evaluating the provisional safety results from an ongoing study of omalizumab. This is an observational study involving approximately 5000 patients treated with omalizumab and 2500 controls; the main objective is to evaluate the long-term profile of omalizumab in patients followed up over a 5-year period.22

Omalizumab is being used successfully in the treatment of chronic urticaria, as evidenced by at least 105 published cases of patients with severe chronic urticaria who have been treated with omalizumab. Moreover, a total of 139 patients have been included in randomized studies comparing the effects of omalizumab with those of a placebo. The most relevant data from these studies are shown in Table 3. The drug has proven effective in cases of autoimmune and non-autoimmune chronic urticaria, with variable results in cases of physical and cholinergic urticaria.

In most published articles omalizumab has been used to treat chronic urticaria following the guidelines for the treatment of severe allergic asthma: between 75 mg and 375 mg at 2- or 4-week intervals, depending on the patient's body weight and baseline IgE levels. Only 1 clinical trial has studied the starting dose of omalizumab in the treatment of chronic non-autoimmune urticaria.46 In this study by Saini and colleagues a total of 90 patients were randomized to receive a single dose of 75, 300, or 600 mg of omalizumab or placebo. Assessment of the response at 4 weeks revealed a mean decrease in the urticaria activity score of 14.6 points in the 600-mg omalizumab group, 19.9 points in the 300-mg group, 9.8 points in the 75-mg group, and 6.9 points in the placebo group. The study demonstrated that 300 mg was the most effective dose in the treatment of urticaria, while the efficacy of the 75-mg dose was similar to that of the placebo. Moreover, a dose of 300 mg was used in most of the experimental studies in which a satisfactory clinical response was obtained. However, it should be noted that Saini and colleagues did not include a 150-mg dose of omalizumab. In a more recent study, 19 patients with chronic urticaria (63% idiopathic, 32% autoimmune) were treated with a fixed dose of 150 mg every 2 weeks; this resulted in complete resolution in 11/19 patients (58%), partial resolution in 5/19 patients (26%), and no response in only 3/19 patients (16%), suggesting that 150 mg is the minimum effective dose for the treatment of chronic urticaria.42

Saini and coworkers did not present conclusive data on maintenance doses and dosing intervals. An attempt by Romano and colleagues33 to increase the interval between doses to over 4 weeks in 2 cases of severe chronic urticaria resulted in clinical relapse and the reappearance of wheals after initial therapeutic success. However, Ferrer and colleagues44 obtained favorable clinical responses in 9 patients with doses of 300 mg omalizumab at variable intervals (monthly in 5 patients, bi-monthly in 1 patient, and even quarterly patient in 3 patients).

The authors declare that no experiments were performed on humans or animals for this investigation.

The authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study.

The authors declare that no private patient data appear in this article.